Boronic acid adducts of rhenium dioxime complexes useful in radiotherapy have been described in European Patent Application 311,891 published Apr. 19, 1989 and have the formula EQU ReX(Y).sub.3 Z
wherein X is an anion, Y is a vicinal dioxime having the formula ##STR1## or a pharmaceutically acceptable salt thereof, and R.sub.1 and R.sub.2 are each independently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containing heterocycle, or together R.sub.1 and R.sub.2 are --(CR.sub.8 R.sub.9).sub.n -- wherein n is 3, 4, 5 or 6 and R.sub.8 and R.sub.9 are each independently hydrogen or alkyl;
Z is a boron derivative having the formula EQU B-R.sub.3
wherein R.sub.3 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl (preferably having 2 to 10 carbons), carboxyalkenyl (preferably having 4 to 19 carbons), hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R.sub.4 R.sub.5 N)alkyl and R.sub.4 and R.sub.5 are each independently hydrogen, alkyl, or arylalkyl, or R.sub.4 and R.sub.5 when taken together with the nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle. The boron derivative "Z" can be thought of as a "cap" for the dioximes at one end of the molecule, through boron-oxygen covalent bonds. The above European Patent Application describes the formation of the "boron capped" rhenium dioxime complexes utilizing rhenium in the plus 3, plus 4, plus 5 or plus 7 oxidation state. European Patent Application 311,891 describes compounds in which rhenium is available in the plus 3 oxidation state such as ReCl.sub.3 (CH.sub.3 CN) (PPh.sub.3).sub.2 and [Re.sub. 2 Cl.sub.8 ](NBu.sub.4).sub.2 wherein Ph=phenyl and Bu=butyl; Re(IV) as K.sub.2 ReCl.sub.6 and Re(VII) as NH.sub.4 ReO.sub.4 or KReO.sub.4 ; Re(V) as [ReOCl.sub.4 ](NBu.sub.4), [ReOCl.sub.4 ](AsPh.sub.4), ReOCl.sub.3 (PPh.sub.3).sub.2 and as ReO.sub.2 -(pyridine).sub.4.sup..sym..
The complexes of European Patent Application 311,891 are prepared with Re(III), Re(IV), Re(V) or Re(VII) ions (in the form of a salt) combined with a source of anion, a boronic acid derivative having the formula ##STR2## or a pharmaceutically acceptable salt thereof, wherein R.sub.7 is hydrogen, alkyl or aryl, and a dioxime having the formula ##STR3## or a pharmaceutically acceptable salt thereof.
More specifically, the boronic acid adducts of rhenium dioxime complexes of European Patent Application 311,891 were prepared from either Re(III), as ReCl.sub.3 (CH.sub.3 CN)(PPh.sub.3).sub.2, Re(IV), as ReCl.sub.6.sup.2, or Re(VII), as ReO.sub.4.sup.-. When the complexes were prepared from Re(III), a reaction time of 15-22 hours was required to form the compounds. When the complexes were prepared from Re(VII), strongly acidic conditions were required, and yields were 0.7 to 5%.
When working with radioactive isotopes of rhenium that have short half-lives, it is important that short reaction times and good yields be obtained. The procedures described in European Patent Application 311,891 either take a long time, give poor yields, or are carried out under strongly acidic conditions. It would be advantageous to devise a high yield procedure for the preparation of these boron capped rhenium dioxime compounds that does not take a long time to carry out. If the compounds could be made in quantitative yield, a separation step could also be avoided. If the reaction conditions were gentle, capping boron ligands that are heat or acid sensitive could be used.
It has now been found that the "boron capped" rhenium dioxime complexes can be formed under very mild conditions if the complexes of the present invention are used as starting materials. The formation of the boron capped rhenium complexes from the complexes of the present invention requires less than one hour, is carried out under mild reaction conditions, and is virtually quantitative. The compounds of this invention can also be capped by other Lewis acids such as derivatives of silicon, aluminum, titanium and tin.